TABLE 1.

A nonexhaustive summary of in silico, in vitro, and in vivo approaches to exploring how the commensal gut microbiota drive individual-specific responses to dietary, prebiotic, and probiotic interventions

	Model	Advantages	Challenges	References
In silico	Machine learning	● Strong predictions● Data-driven	● Predictions specific to training cohort● Mechanistically opaque	Zeevi et al., 2015 (9)Ben-Yacov et al., 2021 (18)
	Metabolic modeling	● Mechanistic● No training data● Predicts function● N-of-1 enabling● Computationally tractable	● Lacks dynamics● Limited by model database● Cannot capture nonmetabolic phenomena	Magnúsdóttir et al., 2017 (32)Diener et al., 2020 (35)Thiele et al., 2020 (36)
	Dynamical modeling	● Capture dynamics● Mechanistic● Predictive	● Computationally intractable for complex ecosystems● Mismatches between sampling timescales and dynamics	Harcombe et al., 2014 (25)Bucci et al., 2016 (26)Mainali et al., 2019 (27)
In vitro	Batch culture	● Cost-effective● Easy to implement● Well suited to high-throughput screening● Ability to monitor metabolite production	● Composition of the medium changes through time● No host absorption or interactions● Difficulty in culturing certain commensals	Liu et al., 2020 (44)Gurry et al., 2021 (45)
	Continuous culture	● Can adjust or maintain medium composition through time● Well suited to comparing steady states before and after treatment● Ability to monitor metabolite production	● Lack of host tissue interaction models● Difficulty in culturing certain commensals	Salgaço et al., 2021 (53)Walton et al., 2012 (47)
	Gut on a chip	● Captures host-tissue interactions	● Experimentally complex	Pimenta et al., 2021 (61)Xiang et al., 2020 (60)
In vivo	Invertebrates	● A complete host–microbe system● Highly experimentally tractable● High degree of replication● Low cost	● Divergent anatomy and physiology from vertebrates● Smaller size can limit the types of possible interventions	Hashmi et al., 2013 (67)Marsh and May, 2012 (68)
	Vertebrates	● Address systemic responses within the context of digestion and absorption● Control over microbial community● Access to host tissues of interest● Control over genetic background and diet	● Nonhuman anatomy (e.g., hindgut fermenters)● Nonhuman physiology● Microbiota specific to each species● Lack of background genetic diversity within many model species	Kim et al., 2021 (69)Kemis et al., 2019 (70)Christoforidou et al., 2019 (73)
	Humans	● Address systemic responses within the context of digestion and absorption● Directly applicable to human outcomes	● Limited access to host tissues of interest● Controlling diet for long-term studies is challenging and expensive● Limited experimental tractability	Lichtenstein et al., 2021 (75)Kane et al., 2021 (77)Nogal et al., 2021 (78)Lancaster et al., 2022 (79)